The invention relates to pancreatin pellets, in particular to pancreatin micropellets, and to a process for their production.
Pancreatin is the term used to define the mixture of enzymes extracted from the pancreatic gland, essentially consisting of lipases, amylase and proteases. The primary starting material for the production of pancreatin is fresh or frozen pig's pancreas, from which only water and fat was originally removed in order to produce pancreatin. Because of the sensitivity of the enzymes, however, processes have been developed in order to obtain the pancreatin in as gentle a manner as possible. A suitable process is described in DE 32 48 588 A1.
Pancreatin is used in particular as an active ingredient for the treatment of digestive disorders due to pancreatic insufficiency. Pancreatin is primarily employed in the dried form as an oral therapeutic agent. It has been observed in this regard that the therapeutic effectiveness of pancreatin administration can be improved if the active ingredient is administered in the form of pellets or micropellets.
Typically, the production of pancreatin pellets involves supplementing the pancreatin with auxiliary materials and binding agents and mixing those components until a homogeneous mixture is obtained. The homogeneous mixture is then introduced into an extruder in which the mixture is transformed into a strand-like extrudate. Finally, the extrudate is introduced into a spheronizer, possibly with the addition of further auxiliary materials, in which the extrudates are transformed into spherical pellets. The pellets are then dried and screened to sort out screened fractions of pellets which are above or below a predetermined size range. The pellets obtained thereby can then be coated with a coating of enteric material.
Upon production, pancreatin precipitates out moistened with solvent and is then normally dried and ground. However, it is disadvantageous to moisten and dry said material several times more in order to shape it, for example upon granulation and spheronization. This takes time and energy and frequently results in loss of quality as the highly sensitive enzymes are damaged.
Until now, pancreatin pellets have been produced from dry pancreatin powder by wet granulation. Normally, auxiliary materials and binding agents are still required in this regard. A process for the production of pancreatin pellets consists in moistening powdered pancreatin with a solvent mixture and shaping it with an extruder into cylindrical raw pellets. The extrudates then also have to be cut to a length of 1.5 mm to 1.7 mm, for example. After drying, those raw pellets are spheronized with a moist pancreatin/coating mixture and then dried again.
A further process for the production of pancreatin micropellets is described, for example, in EP 0 583 726 A2. In that process, prior to extrusion, 100 parts by weight of pancreatin is mixed with 15 to 50 parts by weight of polyethylene glycol 4000 and 10 to 30 parts by weight of an alcohol. The alcohol, for example propanol, is intended to provide the mixture with an extrudable consistency. Prior to transfer into the spheronizer, the extrudates obtained by extrusion are then supplemented with 1.5 to 5 parts by weight of paraffin and a further 1.5 to 10 parts by weight of alcohol. The pellets obtained have a pancreatin content of 65% to 85% by weight, and so the pellets contain at least 15% by weight of auxiliary materials and binding agents.
The auxiliary materials and binding agents required for extrusion may, however, have unwanted side effects. For this reason, constant vigilance is required when selecting the auxiliary materials and binding agents. As an example, it has been observed that the current usual practice of adding mineral oils can no longer be assumed to be immaterial.
For this reason, EP 1 931 317 B1 proposes a process for producing pancreatin pellets without the addition of paraffin. The pancreatin pellets obtained in this case contain 10% to 95% by weight of pancreatin, with at least 5% by weight of auxiliary materials and binding agents such as polyethylene glycol.
However, objections can be expected to be raised against any type of additive on reasoned or even on arbitrary grounds. It would thus be desirable to provide pancreatin in a form which on the one hand can be administered orally and on the other hand is, as far as possible, free from any additives. In addition, a pancreatin concentration of 100% also means that the volume to be administered is a minimum per fixed dose; this makes it easier for the patient to take.
U.S. Pat. No. 4,280,971 A1 discloses a process for the production of pancreatin pellets in which a pliable mass containing a pancreatin powder and an enzyme-friendly solvent is extruded on an extruder, if necessary with cooling, the extrudate is divided into extrudate fragments, dried and then processed further using known methods, for example by applying coatings to the extrudate fragments. However, the process proposes two drying steps, which is not economical, since a mixture of magnesium stearate, pancreatin and isopropanol is produced which is processed on an extruder with bores and cutting equipment to produce extrudates of a predetermined length. The raw pellets obtained thereby are dried in a first step. Next, the raw pellets are spheronized to spherical pellets by applying an isopropanolic solution of polyvinyl pyrrolidone and pancreatin which are then dried further in a second drying step. In that process, it is assumed that the end product has a relatively high residual moisture content because considerable quantities of solvents are employed, but no information is provided to this effect. In addition, the pellets produced have a pancreatin content of more than 65% to 85% by weight, so the pellets may contain up to 15% by weight of auxiliary materials and binding agents; in addition, the pancreatin is initially mixed with magnesium stearate. Furthermore, the process is multi-staged and thus complicated.
EP 0 436 110 A1 discloses a process for the production of spherical pancreatin particles which is characterized by rotating a moist pancreatin mass together with a solvent about a first axis and simultaneously reducing the size of the mass with the aid of knives which rotate about a second axis, wherein a portion of the solvent is removed; the first and the second axes are at an angle to each other, wherein the two axes are arranged perpendicular to each other, so that the mass is subjected to a rolling motion. Overall, the transformation of an already developed and improved pancreatin mass, which is still moistened with solvent, however, into a galenical form is disclosed. The solvent is acetone. The disclosed process for the production of pancreatin particles proposes comminuting the pancreatin mass with the aid of knives, whereby only a portion of the solvent is removed.
U.S. Pat. No. 5,378,462 concerns a pancreatin micropellet core which can be coated with an enteric film and has a pancreatin content of 60% to 85% by weight. The pellet cores are spherical to ellipsoidal in shape, with a diameter or minor axis in the region of 0.7 to 1.4 mm. The pellet cores have a particle size distribution in which at least 80% of the pellet cores have a ratio of the minor axis to the major axis in the region of 1:1 to 1:2. This is intended to result in an improved process by means of which novel pancreatin micropellets coated with an enteric film can be produced with a high bulk density and which have a small particle size which guarantees their successful passage through the pylorus.
DE 20 2010 004 926 U1 discloses Pancreatin pellets which consist exclusively of Pancreatin and are obtained by the following procedure: the pancreas glands originating from pigs or cattle are first comminuted and subjected to autolysis. By filtering the intermediate product thus obtained, a screen filtrate is produced. The enzymes contained in the screen filtrate are precipitated. The mixture thus obtained is filtered and a filter cake is produced which is ground and vacuum-dried until it has a residual moisture content of 0.1 to 03% by weight. Since the extrudable filter cake mass has a residual moisture content/organic solvent residues of approximately 50%, the filter cake is subjected to a heat treatment at 80° C. or less. The heat-treated filter cake is then extruded and then spheronised to give spherical, elliptical or drop-like pellets. In this production method, the processing of the filter cake in the extruder is associated with difficulties insofar as the filter cake exhibits pseudoplastic behaviour to the extent that the filter cake exhibits high flowability under shear load, and therefore difficulties are encountered with further shaping to the point that shaping may no longer be possible and therefore additional binders have to be used.